Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia

Abstract

The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD ¼ 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.

Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

“…PCR of c.DNA, synthesized from RNA isolated from the same individual, showed that mRNA escapes nonsense mediated decay (Fig. 1d), as previously reported [4].…”

“…Here, we describe 13 patients from 7 families with HSP recruited to the 100KGP, who carry 3 truncating variants in UBAP1, a newly identified gene that causes pure forms of juvenile HSP [4]. Variant interpretation analysis had been initially carried out via the 100KGP automated pipeline in known HSP genes [5], and failed to identify a genetic diagnosis in all families.…”

Swimming in Deep Water: Zebrafish Modeling of Complicated Forms of Hereditary Spastic Paraplegia and Spastic Ataxia

“…UBAP1 is a member of the UBA domain family, which includes proteins that have a role in the ubiquitin and ubiquitination pathways (Qian et al, 2001). Seeking to unveil the effects of mutations in UBAP1 in vivo, Farazi Fard et al 2019found that microinjection of CRISPR/Cas9 and sgRNAs against UBAP1 in the transgenic fish with fluorescently labeled motor neuron Tg(Oligo2::DsRed) resulted in misshapen axons and shorter motor neuron length compared with what was observed in controls (Farazi Fard et al, 2019). This work further reinforced the suggestion that "UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs.…”

“…SPG80 is a juvenile-onset neurological disorder characterized by a progressive spasticity and hyperreflexia. Some affected subjects also showed cerebellar signs and mild cognitive impairment (Farazi Fard et al, 2019). All affected individuals carried heterozygous non-sense or frameshift mutations in the UBAP1 (ubiquitin-associated protein 1) gene.…”

Truncating variants in UBAP1 associated with childhood‐onset nonsyndromic hereditary spastic paraplegia

“…We report frameshift UBAP1 variants in five individuals with childhood-onset AD HSP. While preparing this manuscript, an article describing truncating variants in UBPA1 causing HSP was published (Farazi Fard et al, 2019), with eight different truncating mutations from 10 families, including a recurrent de novo c.426_427delGA variant in two families, which is identical to the variant in Families 1-4 reported here (Table 1). Therefore, with our patients, there are now six HSP families with the c.426_427delGA variant identified, providing additional evidence for a mutational hotspot in UBAP1.…”